A new family of quinoline and quinoxaline analogues of combretastatins Concepci  on P erez-Melero, Ana B. S. Maya, Benedicto del Rey, Rafael Pel aez, Esther Caballero and Manuel Medarde * Laboratorio de Qu  ımica Org anica y Farmac eutica, Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain Received 18 November 2003; revised 22 April 2004; accepted 29 April 2004 Available online 25 May 2004 Abstract—The 3-hydroxy-4-methoxyphenyl ring of combretastatin A-4 can be replaced by a 2-naphthyl moiety without significant loss of cytotoxicity and inhibition of tubulin polymerization potency. In this paper we show that the 6- or 7-quinolyl systems can in turn replace both cyclic moieties, keeping in the first case most of the potency as cytotoxic agent and in the second case as inhibitor of tubulin polymerization, related to the activities displayed by model compounds. Ó 2004 Elsevier Ltd. All rights reserved. Microtubules generated by polymerization of tubulin a,b-dimers are the main constituents of the mitotic spindle, whose formation and activity are required for chromosome segregation during mitosis and for other cell processes. 1 Natural and synthetic compounds of varied structures have been shown to inhibit tubulin polymerization through interaction with the protein at different binding sites; the colchicine, taxol and Vinca alkaloids sites are the best known of them. 2 Among the ligands of the colchicine binding site, combretastatins 3 are highlighted as strongly cytotoxic 4 and antiangio- genic 5 agents, combretastatin A-4 (CS A-4) being the most potent member of this family 6 (Fig. 1). The main problem associated with this class of compounds is their low aqueous solubility. Therefore, efforts have been directed at obtaining soluble derivatives, leading to combretastatin A-4 phosphate prodrug, 7 which cur- rently is in phase II clinical trials. From different SAR studies on combretastatins 8;9 it was deduced that a 3,4,5-trimethoxyphenyl ring and a 4-methoxy-3-X-substituted phenyl ring systems, sepa- rated by a two atoms bridge in a cis disposition, is the common structural characteristic for these compounds to be active (X ¼ H, OH, NH 2 and their aminoacyl, phosphate or other derivatives for solubilizing pur- poses). It has been reported that lipophilicity is an important feature for ligand binding, showing a good correlation between log P and binding to tubulin, 8 al- though there are also contradictory reports. 9 We have recently shown that one of the oxygenated A or B phenyl rings of CS A-4 can be replaced by a naphthalene moiety keeping high potency, 10 whereas substitution of both A and B rings leads to an inactive compound. Following these results, we proceeded further in order to determine which one of the CS A-4 rings is actually best replaced by the naphthalene in the CS A-4 analogues. We then prepared different families of compounds that were tested for cytotoxicity and inhibition of tubulin polymerization, 11 leading to the conclusion that the naphthalene system is a good surrogate for the 3-hy- droxy-4-methoxyphenyl ring B, producing much less potent derivatives when the naphthalene replaces the trimethoxyphenyl ring A (Fig. 1). Even though the introduction of a naphthalene system keeps most of the potency of combretastatins and increases their lipophilicity, their low aqueous solubility is a main drawback in order to assay these compounds in vivo. To extend our studies to other bicyclic systems as surrogates of the B ring of CS A-4 and to increase their poor solubility, we have designed a new family of analogues replacing the naphthalene moiety by a quinoline or quinoxaline system and keeping the Keywords: Combretastatins; Quinolines; Tubulin polymerization inhibition. * Corresponding author. Tel.: +34-923-294528; fax: +34-923-294515; e-mail: medarde@usal.es 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.04.098 Bioorganic & Medicinal Chemistry Letters 14 (2004) 3771–3774